Tyrosinase is a critical target to modulate pigmentation of skin. It is possible to lighten the colour of human skin by use of cosmetic or pharmaceutical compositions containing tyrosinase inhibitors. Tyrosinase is a copper bound enzyme and inhibitors that target this enzyme are potential skin lightening agents. The cosmetic and pharmaceuticals industry has always been interested in compounds which inhibit the activity of tyrosinase.
Consumers of cosmetic compositions desire even skin tone, no or minimal age spots, absence of hyperpigmentation and overall a lighter skin tone. There are biological actives that reduce the activity of melanocyte cells present in human skin. Melanocytes are present in the basal layer of epidermis and they produce melanin and export it, in small export vesicles, called melanosomes, to neighbouring keratinocytes. Compounds that reduce synthesis melanin when topically applied to the skin can lighten the skin over a period. Tyrosinase is one of the many targets to regulate production of melanocytes. However, some of the effective inhibitors of tyrosinase are not too safe and they may cause melanocyte cell death, permanent depigmentation, irritation or allergic reactions.
Therefore, there is need for safe and effective inhibitors of tyrosinase.
K M Valikhanov et. al. Synthesis of New Derivatives based on benzo-crown ethers and some natural amines” Chemistry of Natural Compounds, Vol 34, No. 4, 1 Jan. 1998. pages 613-615 discloses the use of certain crown ether derivatives.
Mirkhodjaev U Z et. al: On the Mechanism of Action of Dibenzo-18-Crown-6-diacyl derivatives on Malignant Tumours”, Journal Of Inclusion Phenomenon And Macrocyclic Chemistry, 53(3), 1 Nov. 2005, pages 191-196 discloses the use of a crown ether in cancer treatment.
U.S. Pat. No. 5,965,524 A (Burke et. al, 1999) discloses analogs of viscosin, pharmaceutical compositions thereof and to methods of using viscosin and crown ether analogs thereof as biosurfactants and as antibacterial, antiviral and antitrypanosomal therapeutic compounds. In particular, compositions that inhibit thegrowth of the pathogens Mycobacterium tuberculosis, 
WO02/08174 A1 (Riley Patrick) discloses novel mono- and dihydroxy phenylethylamine derivatives useful in treating melanoma. The compounds are prodrugs which are inactive until metabolised by enzymes expressed by host melanoma cells. The invention allows a greater amount of active agent to be used while reducing systemic side effects.
EP 2295403 A1 (Corum Inc, 2011) discloses compounds with a carboxyl acid group and an amide group also containing the tertiary amino groups. The carboxyl acid group having a partial negative charge attracts the tertiary amino group to form a quaternary ammonium salt structure. These compounds have a mushroom tyrosinase-inhibition effect and have the potential to use in the cosmetics for skin whitening.
Anca Paun et. al: “Synthesis and microbiological evaluation of several benzocaine derivatives”. Compus Rendus—Chimie, Vol 16 no. 7. 1 Jul. 2013, pages 665-671 discloses crown ether derivatives of benzocaine, its antimicrobial and antioxidant properties.
CN 103130791 A (Jiangsu et. al, 2013) discloses crown ether derivatives of benzamide and their anticancer properties.
D V Kutnetsov et. al: Synthesis, extraction and transport properties of dibenzo-18-crown-6 modified with the fragments of 2-amino-1,3,-thiadiazol and kojic acid” Russian Journal Of General Chemistry, 78(10), 1 Oct. 2008, 1924-1928 discloses certain crown ethers in the preparation of new antibacterial agents.
FR2921828 A1 (Oreal, 2009) discloses a cosmetic or pharmaceutical composition comprising a polycondensate obtained by the reaction of one or more polyols comprising hydroxyl groups.
While human tyrosinase has been the primary subject of research, others like mushroom tyrosinase are also equally important. Mushroom tyrosinase is similar to plant polyphenol oxidases. These forms are present in food products and beverages and believed to be responsible for darkening or browning. Therefore, inhibition of mushroom tyrosinase is also important for the foods and refreshments industry.
We have now found that certain crown ethers have the ability to inhibit the activity of tyrosinase, human as well as mushroom. Such crown ethers are potential actives for cosmetic compositions as well as food and beverage compositions for inhibitory activity of tyrosinase.